Diabetic nephropathy is one of the most dreaded complications of diabetes mellitus. About 30% to 50% of patients with type I (insulin-dependent) diabetes mellitus and somewhat fewer of those with non-insulin-dependent diabetes mellitus develop this complication. The major risk factors contributing to the development of diabetic nephropathy are metabolic control (poor glycemic control), hemodynamic factors (hypertension, elevated renal flow, intraglomerular capillary pressure) and genetic susceptibility. The nonobese diabetic (NOD) mouse spontaneously develops type I (insulin-dependent) diabetes secondary to islet beta cell destruction by infiltrating lymphocytic and monocytic cells (insulitis). Shortly after the appearance of diabetes (both in males and females), the NOD mouse develops renal lesions which consist of diffuse mesangial sclerosis associated with glomerular hypertrophy, thickening of glomerular basement membrane, accumulation of type IV collagen in mesangial areas and the development of albuminuria. These findings closely mimic the glomerular lesions found in human diabetic patients. The NOD mouse, therefore, provides a model to investigate the pathogenesis of the early events of diabetic glomerulosclerosis. The NOD mouse represents a unique opportunity to study the interdependency or lack thereof between insulin-dependent diabetes mellitus and glomerulosclerosis in a genetically defined animal model. Our preliminary observation suggests the existence of an independent glomerulosclerosis gene of diabetes in the NOD mouse. The unique point of our project is the use of backcross animals of NOD mice with a wild mouse strain, Mus spretus Spain. Mus spretus Spain represent polymorphisms at many loci and do not develop diabetes and glomerulosclerosis. Our proposed studies aim to define the mode of inheritance of the glomerular lesions in these mice in the following ways: a) Establishment of parallel lines of 2nd backcross animals of NOD with Mus spretus Spain, and the penetrance of diabetes and insulitis b) Inheritance of glomerulosclerosis in F1, 1st and 2nd backcross animals of NOD with Mus spretus Spain c) Interdependency or lack thereof between the diabetogenic genes and the degree of glomerulosclerosis d) Linkage analysis of microsatellite and major satellite markers in the telomere and centromere with the kidney disease of diabetes mellitus using polymerase chain reaction (PCR) and centromere distribution (in situ hybridization) analyses. We would like to emphasize that the principal investigator in this grant proposal has never received independent research grant support from the PHS.